Tae Sook Hwang

Surgical Results of Thyroid Nodules according to a Management Guideline Based on the BRAFV600E Mutation Status

CONTEXT In Korea, where PTC comprises about 90-95% of the reported thyroid cancers, the prevalence of BRAF(V600E) mutation in papillary thyroid carcinoma (PTC) is above 80%. OBJECTIVE We analyzed the surgical result according to a management guideline based on the BRAF(V600E) mutation status of thyroid nodules. DESIGN A total of 865 thyroid nodules were prospectively analyzed for their cytology and BRAF(V600E) mutation status by pyrosequencing. For the patients who had a diagnosis of atypical cells of undetermined significance (ACUS), we recommended surgery when there was positivity for BRAF(V600E) mutation or the nodules were clinically suspicious. RESULTS Among 865 cases, 504, 141, 54, 140, 10, and 16 were diagnosed as benign, ACUS, suspicious for malignancy, malignant, suspicious for follicular neoplasm, and nondiagnostic, respectively. None of the 504 benign, 45 (31.9%) of the 141 ACUS, 46 (85.2%) of the 54 suspicious for malignancy, 129 (92.1%) of the 140 malignant, and one (10%) of the 10 suspicious for follicular neoplasm cases showed BRAF(V600E) mutation. Surgery was recommended to all 45 patients with BRAF(V600E) mutation-positive ACUS nodules; among them, 30 patients underwent surgery, 29 had PTC, and one had nodular hyperplasia. All the patients diagnosed as suspicious for malignancy or malignant were advised to undergo an operation, and they turned out to have PTCs regardless of their BRAF(V600E) mutation status. CONCLUSIONS We found that performing BRAF(V600E) mutation analysis on the fine-needle aspiration biopsy specimens was of great help to make a therapeutic decision for thyroid nodules when the fine-needle aspiration biopsy results were equivocal.

Clinical and Pathological Features and the BRAFV600E Mutation in Patients with Papillary Thyroid Carcinoma with and without Concurrent Hashimoto Thyroiditis

BACKGROUND It has been reported that patients with papillary thyroid carcinoma (PTC) have a high incidence of background Hashimoto thyroiditis (HT); however, the linkage of HT to PTC is controversial. Recent studies have shown that the prevalence of activating point mutations in BRAFV600E is much higher (73-86%) in Korea than in Western countries (29-69%), and associated with a poor prognosis in PTC. The purpose of the present study was to investigate the frequency of the BRAFV600E mutation in PTC with and without HT, and to determine clinical and pathological features that were associated with concomitant HT and PTC. METHODS Fine-needle aspiration slides from 101 patients with surgically confirmed PTC were studied. The DNA was extracted from the atypical cells that were scraped from slides. It was then analyzed for the BRAFV600E mutation by pyrosequencing. In addition, the presence of background HT in surgical specimens and other clinical and pathological features of the patients were characterized. RESULTS HT was present in 37 (36.6%) of the patients. The BRAFV600E mutation was present in 27 (72.9%) of patients with HT but was present in 61 (95.3%) of patients without HT ( p#0.01). The inverse correlation of concurrent HT with the BRAFV600E mutation was significant for both males and females ( p < 0.01). The presence of background HT was not associated with tumor size, extrathyroidal invasion, lymph node (LN) metastasis, or tumor stage. The patients were younger in the group without background HT (44.1 +/- 13.2 vs. 49.8 +/- 13.9, p 1/40.05). The BRAFV600E mutation was present in 88 (87.1%) of the 101 patients with PTC. The presence of the BRAFV600E mutation was significantly associated with LN metastasis ( p < 0.02; odds ratio, 6.24; 95% confidence interval, 1.51-25.79). CONCLUSION In Korean patients with PTC, the BRAFV600E mutation is associated with a lower frequency of background HT and a high frequency of LN metastasis.

The BRAFV600E mutation is associated with malignant ultrasonographic features in thyroid nodules

Context  Several ultrasonographic (US) features of thyroid nodules have been reported to predict malignancy. The BRAFV600E mutation is a useful diagnostic marker for differentiating papillary thyroid carcinoma from benign thyroid nodules, especially in BRAFV600E‐prevalent populations such as in Korea.

BRAF Mutation Analysis and Sonography as Adjuncts to Fine-Needle Aspiration Cytology of Papillary Thyroid Carcinoma: Their Relationships and Roles

OBJECTIVE The objective of our study was to evaluate the relationships between BRAF mutation status, sonography findings, and fine-needle aspiration cytology features in patients with papillary thyroid carcinoma (PTC) and to evaluate the diagnostic merits of BRAF mutation status and sonography findings as adjuncts to cytologic diagnoses. MATERIALS AND METHODS From March 2006 through June 2008, clinicopathologic factors, sonography findings, cytology results, and BRAF mutation status were evaluated in 524 patients (437 women and 87 men) with 553 thyroid nodules; of the 170 malignant nodules, 164 were PTCs. Clinicopathologic factors, sonography findings, and cytology results were correlated with BRAF status. The diagnostic sensitivities and specificities of sonography, cytology, and BRAF analysis and their combinations were compared. RESULTS The V600E mutation of BRAF (BRAF(V600E)) was detected in 141 of 170 malignant thyroid nodules (82.9%) (140 PTCs and one follicular variant of PTC). Multiple logistic regression revealed that BRAF status was not associated with sonography features with the exception of a negative relation between BRAF(V600E) and an irregular shape (p = 0.004). An indeterminate cytology result was more frequent for BRAF-negative PTC than BRAF-positive PTC (p = 0.035). By adding BRAF status to cytology, diagnostic sensitivity for PTC was significantly increased (94.1%) as compared with cytology alone (81.8%) (p < 0.001). The triple combination-that is, sonography, cytology, and BRAF analysis-showed higher sensitivity than BRAF plus cytology (98.2% vs 94.1%, respectively) (p < 0.05). CONCLUSION The sonography features of PTC, other than an irregular shape, are not related to BRAF status and the combination of sonography and BRAF testing would increase the diagnostic accuracy of cytologic diagnoses of PTC.

Differential expression of Bcl-2, Bcl-XL and p53 in colorectal cancer

Aims:  The balance between proliferation and apoptosis is often disturbed in cancer. The aim of this study was to investigate the possible role of Bcl‐2 gene family members and p53 as prognostic factors in a series of colorectal cancer.

Prognostic Significance of TERT Promoter Mutations in Papillary Thyroid Carcinomas in a BRAF(V600E) Mutation-Prevalent Population.

BACKGROUND The role of telomerase reverse transcriptase (TERT) promoter mutations in differentiated thyroid cancer has been well established. These mutations have a significantly higher prevalence in aggressive thyroid tumors, including widely invasive oncocytic carcinomas, poorly differentiated carcinomas, and anaplastic thyroid carcinomas. Interestingly, in some studies, TERT mutations were found to be more common in tumors with a BRAF(V600E) mutation. However, mutational analysis of TERT promoter mutations in thyroid tumors has not been previously performed for patients in Korea, where the BRAF(V600E) mutation in papillary thyroid carcinoma (PTC) is particularly prevalent. This study analyzed TERT promoter mutations in various thyroid tumors and examined their relationship with clinicopathologic factors and the BRAF(V600E) mutation in PTC cases. METHODS Using 242 preoperative fine-needle aspiration biopsy specimens (including 207 PTCs) with confirmed histopathological diagnosis of the biopsied thyroid nodules, the TERT promoter status (C228T and C250T) was analyzed, and the relationship with clinicopathologic factors and the BRAF(V600E) mutation in PTC cases was examined. RESULTS Of 242 patients, 14.5% (30/207), 26.7% (4/15), 50% (1/2), and 60% (2/5) of PTCs, follicular thyroid carcinomas, poorly differentiated carcinomas, and anaplastic thyroid carcinomas harbored a TERT(C228T) mutation, respectively. The TERT(C228T) mutation was associated with recurrence (p = 0.03). However, no association with other clinicopathologic factors in PTC was found. Coexistence of TERT(C228T) and BRAF(V600E) mutations was found in 13.0% of PTCs and was significantly associated with older age and advanced stage compared with the group negative for either mutation. The TERT(C228T) mutation status was an independent prognostic factor for recurrence-free survival (hazard ratio = 3.08 [confidence interval 1.042-9.079]; p = 0.042) in patients with PTC in multivariate analysis. CONCLUSIONS Identification of TERT promoter mutations in preoperative fine-needle aspiration biopsy specimens may help in better characterizing the prognosis and triaging thyroid cancer patients for appropriate treatment.

RAS mutations in indeterminate thyroid nodules are predictive of the follicular variant of papillary thyroid carcinoma.

RAS mutations are the most common mutations in thyroid nodules with indeterminate cytology by fine‐needle aspiration cytology (FNAC), and are mutually exclusive with BRAF mutations. However, the diagnostic utility of RAS mutation analysis is uncertain. We evaluated the diagnostic utility of RAS mutation analysis in indeterminate thyroid nodules.

Preoperative RAS Mutational Analysis Is of Great Value in Predicting Follicular Variant of Papillary Thyroid Carcinoma

Follicular variant of papillary thyroid carcinoma (FVPTC), particularly the encapsulated subtype, often causes a diagnostic dilemma. We reconfirmed the molecular profiles in a large number of FVPTCs and investigated the efficacy of the preoperative mutational analysis in indeterminate thyroid nodules. BRAF V600E/K601E and RAS mutational analysis was performed on 187 FVPTCs. Of these, 132 (70.6%) had a point mutation in one of the BRAF V600E (n = 57), BRAF K601E (n = 11), or RAS (n = 64) genes. All mutations were mutually exclusive. The most common RAS mutations were at NRAS codon 61. FNA aspirates from 564 indeterminate nodules were prospectively tested for BRAF and RAS mutation and the surgical outcome was correlated with the mutational status. Fifty-seven and 47 cases were positive for BRAF and RAS mutation, respectively. Twenty-seven RAS-positive patients underwent surgery and all except one patient had FVPTC. The PPV and accuracy of RAS mutational analysis for predicting FVPTC were 96% and 84%, respectively. BRAF or RAS mutations were present in more than two-thirds of FVPTCs and these were mutually exclusive. BRAF mutational analysis followed by N, H, and KRAS codon 61 mutational analysis in indeterminate thyroid nodules would streamline the management of patients with malignancies, mostly FVPTC.

Primary pure squamous cell carcinoma of the thyroid: Report and histogenic consideration of a case involving a BRAF mutation

Primary squamous cell carcinoma of the thyroid (SCC‐T) is extremely rare. Its clinical presentation is similar to that of anaplastic carcinoma. Metastasis or extension from the head and neck area should be ruled out, as patients with SCC‐T have a poorer prognosis than patients who have a thyroid extension from an adjacent tumor. An 87‐year‐old man presented with a longstanding painless mass in the right thyroid and had experienced 2 months of pain upon swallowing. A right lobectomy was performed with resection of thyroid cartilage, cricoid cartilage, a portion of the first to third tracheal ring and the right neck lymph node. A histological examination revealed pure SCC. The tumor cells showed diffuse immunoreactivity to CK5/6, CK19 and p63. Immunoreactivity to EMA and p53 was focally positive. TTF‐1, galectin 3 and thyroglobulin immunoreactivity was restricted to the non‐neoplastic thyroid tissue. Both tumor cells and non‐neoplastic follicular cells were negative for CD5. The MIB‐1 index was 36%. DNA extracted from the tumor identified a BRAF V600E mutation in exon 15 and a BRAF G468A mutation in exon 11, whereas DNA from non‐tumorous cells did not contain a mutation. These molecular findings may suggest a direct transformation from papillary carcinoma to SCC‐T.

ERG Immunohistochemistry as an Endothelial Marker for Assessing Lymphovascular Invasion

Background ERG, a member of the ETS family of transcription factors, is a highly specific endothelial marker. We investigated whether the use of ERG immunostaining can help pathologists detect lymphovascular invasion (LVI) and decrease interobserver variability in LVI diagnosis. Methods Fifteen cases of surgically resected colorectal cancers with hepatic metastasis were selected and the most representative sections for LVI detection were immunostained with ERG, CD31, and D2-40. Eight pathologists independently evaluated LVI status on hematoxylin and eosin (H&E) and the corresponding immunostained sections and then convened for a consensus meeting. The results were analyzed by kappa (κ) statistics. Results The average rate of LVI positivity was observed in 43% with H&E only, 10% with CD31, 29% with D2-40, and 16% with ERG. Agreement among pathologists was fair for H&E only (κ=0.27), D2-40 (κ=0.21), ERG (κ=0.23), and was moderate for CD31 (κ=0.55). Consensus revealed that ERG nuclear immunoreactivity showed better visual contrast of LVI detection than the other staining, with improved agreement and LVI detection rate (κ=0.65, LVI positivity rate 80%). Conclusions The present study demonstrated a superiority with ERG immunostaining and indicated that ERG is a promising panendothelial marker that might help pathologists increase LVI detection and decrease interobserver variability in LVI diagnosis.